Possible catecholaminergic-opioidergic control of blood pressure during muscular contraction.

The effects of an alpha 2 adrenoceptor blocker, yohimbine, and an alpha 1 adrenoceptor blocker, phenoxybenzamine, and the central alpha 2 adrenoceptor agonist, clonidine, on changes in arterial blood pressure and heart rate were studied during fatiguing muscular contractions to determine whether an adrenergic-opioidergic system might be involved in the mediation of cardiovascular function. Fatiguing contractions of the gastrocnemius and plantaris muscles of cats caused an increase in mean arterial blood pressure to 150-170 mmHg from resting values of 110-120 mmHg. Injection of clonidine into the cerebral aqueduct eliminated the increase in blood pressure; this effect was dose dependent. Naloxone antagonised the effects of the highest dose of clonidine (5 micrograms). Injections of yohimbine (1 microgram) into the cerebral aqueduct had no significant effect on this pressor response. Yohimbine (1 microgram) effectively counteracted the antipressor effects of clonidine when the two drugs were injected together until higher doses of clonidine (2-5 micrograms) were used. Phenoxybenzamine had no effect on the pressor response itself but unlike yohimbine was able to attenuate the effects of clonidine only when injected together. These data suggest that activation of muscle ergoreceptor afferent nerve fibres (group III and IV fibres) during muscular contractions may cause an increase in arterial blood pressure by interfering with an inhibitory adrenergic-endorphinergic pathway in the medullary region of the brainstem.

The low dose (1-microg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency.

Currently, the most popular test for adrenal insufficiency is the conventional rapid ACTH stimulation test (250 microg ACTH). This method is quick and safe, but incorporates a dose of ACTH that is supraphysiological and capable of transiently stimulating the adrenal cortex in many patients with documented central adrenal insufficiency. In recent years, several investigators have published substantial evidence for a more sensitive ACTH stimulation test using a lower dose of ACTH (1 microg). Further analysis of these data, including the calculation of likelihood ratios, demonstrates that the 1-microg test performs significantly better than the 250-microg test compared to the gold standard, insulin tolerance test. We suggest that the 1-microg ACTH stimulation test replace the conventional 250-microg test when evaluating for central adrenal insufficiency. A cortisol level below 500 nmol/L after 30 min signifies impaired adrenocortical reserve. An insulin tolerance test should be performed if this low dose test results in a borderline value and the diagnosis is questioned. The 1-microg test should not be used if recent pituitary injury is suspected. Pharmaceutical companies should be encouraged to provide synthetic ACTH in 1-microg vials.

The effects of mild ethanol intoxication on the hypothalamic-pituitary-adrenal axis in nonalcoholic men.

Historically, ethanol exposure has been thought to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. However, recent studies have demonstrated decreased responsiveness to metyrapone and insulin-induced hypoglycemia in alcoholic subjects. The present study investigated in more detail the effect of acute ethanol ingestion (0.75 g/kg) on the HPA axis in healthy nonalcoholic men (n = 14). In study 1, plasma ACTH/cortisol levels were determined basally and every 30 min over a 180-min period after the ingestion of placebo or ethanol (n = 8). When the subjects were analyzed as a group, ethanol did not alter ACTH or cortisol levels. However, in two of eight subjects, ethanol ingestion was accompanied by a rise in plasma ACTH. In study 2, ethanol or placebo was ingested over 15 min, and 1 microgram/kg ovine (o) CRH was administered (n = 9). Hormone levels were determined at 20 min before and 0, 15, 30, 60, and 90 min after iv oCRH. Compared to responses to placebo, plasma ACTH responses to oCRH were blunted during the ethanol session [peak ACTH, 14.2 +/- 1.4 vs. 20.3 +/- 3.1 pmol/L (P = 0.036); peak value minus baseline (delta), 7.3 +/- 1.4 vs. 13.4 +/- 2.6 pmol/L (P = 0.017); delta divided by baseline x 100, 131 +/- 28 vs. 197 +/- 29% (P = 0.041); area under the ACTH curve, 1082 +/- 116 vs. 1529 +/- 232 pmol/min.L (P = 0.024)]. Ethanol ingestion also significantly blunted plasma cortisol levels after oCRH compared to placebo treatment. In study 3, ethanol or placebo was ingested over 15 min, and 0.25 microgram ACTH-(1-24) was administered (n = 5). Cortisol levels, determined 20 min before and 0, 30, 60, and 90 min after ACTH treatment, were not altered by ethanol administration. In summary, mildly intoxicating doses of ethanol did not stimulate the HPA axis in six of eight subjects. However, mild intoxication significantly impaired oCRH-stimulated ACTH/cortisol secretion. We speculate that mild intoxication with ethanol may impair the ability of the HPA axis to respond to physiological stressors.

Elevated plasma adrenocorticotropin concentration as evidence of limited adrenocortical reserve in patients with adrenomyeloneuropathy.

Adrenal insufficiency occurs in approximately two thirds of patients with adrenomyeloneuropathy. Its development may precede or follow the onset of neurological disease. To define the sensitivity of various tests of adrenal cortical function, we reviewed adrenocortical function tests in 28 patients with adrenomyeloneuropathy who had normal ACTH stimulation tests at the time of enrollment into an ongoing dietary study. Endocrine studies performed at 6-month intervals included a conventional ACTH stimulation test, plasma ACTH and cortisol concentrations, and 24-h urinary cortisol and aldosterone excretion rates. Eleven patients (39%) developed an elevated plasma ACTH concentration after a median follow-up of 3 yr. Their 24-h urinary cortisol and plasma basal and ACTH-stimulated cortisol concentrations were all normal. The mean basal cortisol level tended to be lower in patients who had increased plasma ACTH levels than in patients who maintained a normal plasma ACTH concentration during the study period (408 +/- 22 vs. 491 +/- 33 nmol/L; P = 0.05). Patients who had an increased plasma ACTH concentration and symptoms consistent with adrenal insufficiency had a lower mean 24-h urinary free cortisol level than those with normal plasma ACTH (196 +/- 22 vs. 281 +/- 30 nmol/day; P < 0.05). Plasma ACTH concentrations were persistently elevated in six patients in whom subsequent values were available. One individual later developed a subnormal ACTH-stimulated cortisol concentration consistent with overt adrenal insufficiency. Our results suggest that conventional provocative and integrative tests of adrenocortical function may not be sufficient to identify patients with adrenomyeloneuropathy who have compensated adrenal hypofunction. An elevated plasma ACTH concentration may represent an early marker for adrenocortical dysfunction and incipient adrenal insufficiency in AMN patients.

Outcomes of therapy for Cushing's disease due to adrenocorticotropin-secreting pituitary macroadenomas.

We reviewed our experience with 21 patients who had Cushing's disease due to ACTH-secreting macroadenomas to clarify the natural history of this disease. All patients had typical clinical and biochemical features of ACTH-dependent hypercortisolism. Their mean maximal tumor diameter was 1.6 +/- 0.1 cm, and the range was 1.0-2.7 cm. Six patients had cavernous sinus invasion, three had invasion of the floor of their sella, and nine had suprasellar extension. The observed remission rate was significantly lower in macroadenoma patients than in microadenoma patients (67% vs. 91%; chi 2 = 5.7; P < 0.02). Cavernous sinus invasion (odds ratio, 35; 95% confidence interval, 2.6-475; P < 0.008) and presence of a maximum tumor diameter 2.0 cm or more (odds ratio, 12.9; 95% confidence interval, 1.4-124; P < 0.02) emerged as the only predictors of residual disease after surgery. The observed recurrence rate was significantly higher in macroadenoma patients than in microadenoma patients (36% vs. 12%; chi 2 = 4.2; P < 0.05). Macroadenoma patients tended to suffer from recurrences earlier than did microadenoma patients (16 vs. 49 months). Stepwise multiple logistic regression did not identify any predictors of disease recurrence in macroadenoma patients. Eight macroadenoma patients underwent a total of nine repeat surgical procedures, but none of these resulted in clinical remissions. Only four of seven (57%) patients followed for a sufficient period of time achieved normal urinary free cortisol levels after conventional radiotherapy. Three (75%) of these four patients had re-recurrent hypercortisolism after brief periods of eucortisolism. Pharmacological agents and adrenalectomy were effective in the management of hypercortisolism in patients with residual and recurrent disease. Our results indicate that ACTH-secreting macroadenomas are more refractory to conventional treatments than are ACTH-secreting microadenomas.

Assessment of adrenal function in women heterozygous for adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked recessive disorder that destroys the white matter of the brain and is associated with adrenal insufficiency. The prevalence of adrenal dysfunction in 71 women carriers of the X-linked ALD gene was studied. These subjects were identified initially on the basis of being obligate carriers of the X-linked trait by pedigree analysis and were confirmed by plasma very long chain fatty acid levels consistent with a heterozygote status. One subject had well documented overt adrenal insufficiency, diagnosed and treated since age 9 yr. Among the remaining women, the mean serum 0800 h and 1 h post-ACTH cortisol concentrations [16 +/- 7 (+/-SD) and 34 +/- 8 micrograms/dL, respectively] were normal. All subjects had normal ACTH-stimulated serum cortisol levels, i.e. more than 20 micrograms/dL. However, 4 subjects (6%) had subnormal ACTH-stimulated aldosterone concentrations (mean, 9 +/- 6 vs. 42 +/- 16 ng/dL for other subjects; P = 0.001, by Mann Whitney rank sum test). Three of these women (75%) were taking nonsteroidal antiinflammatory agents (NSAIDs), whereas only 4 of 67 (6%) subjects with normal aldosterone responsiveness were NSAIDs users (P < 0.01, by Fisher's exact test). Thus, NSAIDs use was associated with increased risk of hypoaldosteronism (odds ratio, 50.2; 95% confidence interval, 3.3-266; P < 0.002). Three of these four women had symptoms consistent with mineralocorticoid deficiency. Serum sodium and potassium concentrations were normal in all subjects. Basal and metyrapone-stimulated plasma ACTH concentrations were also normal in adequately tested subjects with and without mineralocorticoid insufficiency. Five of eight subjects (63%) who underwent testing with synthetic ovine CRH (oCRH) had abnormalities. Three did not meet the criteria for adequate cortisol stimulation (i.e. > 20 micrograms/dL) and had peak ACTH levels greater than 30 pg/mL. Two other subjects had exaggerated ACTH responses with normal cortisol levels. There were no significant differences in the mean or median levels of very long chain fatty acid, C26:0, C24/22 ratios, or C26/22 ratios among the entire subject group, the subgroup with blunted aldosterone responses to ACTH, and the subgroup with blunted responses to oCRH (P > 0.05, by ANOVA and Kruskall-Wallis test for C26, C24/22 ratio, and C26/22 ratio). We conclude that 1) adrenal cortical insufficiency rarely develops in ALD heterozygotes; 2) isolated mineralocorticoid insufficiency can occur in ALD heterozygotes, as has been previously reported to occur with autoimmune and acquired immunodeficiency syndrome-related adrenal dysfunction; 3) ALD heterozygosity may predispose these individuals to NSAID-related hypoaldosteronism; and 4) a subclinical decrease in glucocorticoid reserve, as measured by oCRH testing, may be present in a majority of these women. Aldosterone levels should be included in the ACTH stimulation testing when seeking evidence of adrenal insufficiency in affected women. NSAIDs should be considered a risk factor for the development of hypoaldosteronism in women heterozygous for ALD.

Pituitary adenomas: screening for G alpha q mutations.

Mutant, guanosine triphosphatase-deficient, alpha-subunits of the G protein, Gs, gsp ocogene have been discovered in 40% of GH-secreting pituitary adenomas. Therefore, we hypothesized that a novel G protein class, G alpha q, involved in pituitary signal transduction, might be involved in pituitary tumorigenesis. Recombinant mutations of G alpha q result in constitutive activation of phospholipase C and have transforming activity. Therefore, we screened tumor samples from 37 pituitary adenomas for the presence of activating mutations of the G alpha q gene. Importantly, our sample contains 8 FSH and LH adenomas. In the pituitary gland, FSH and LH are linked to the GnRH-G alpha q signaling cascade, making these tumors a logical choice for screening for G alpha q mutations. Complementary DNA (cDNA) was synthesized by RT-PCR with G alpha q specific primers to exclude pseudogene transcripts. Fragments of G alpha q cDNA-encompassing residues (Arg183, Gln209) were screened by single-strand conformation polymorphism and then sequenced in both directions. No mutations were detected. We conclude that mutations in these regions of the G alpha q cDNA occur infrequently, if at all, in human pituitary adenomas. Alternative mechanisms underlying pituitary tumorigenesis should be explored.

Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production.

Recent data suggest an interaction between the renin-angiotensin-aldosterone system and fibrinolysis. Although previous work has focused on the effect of angiotensin II (Ang II) on plasminogen activator inhibitor (PAI-1) expression, the present study tests the hypothesis that aldosterone contributes to the regulation of PAI-1 expression. To test this hypothesis in vitro, luciferase reporter constructs containing the human PAI-1 promoter were transfected into rat aortic smooth muscle cells. Exposure of the cells to 100 nmol/L Ang II resulted in a 3-fold increase in luciferase activity. Neither 1 micromol/L dexamethasone nor 1 micromol/L aldosterone alone increased PAI-1 expression. However, both dexamethasone and aldosterone enhanced the effect of Ang II in a dose-dependent manner. This effect was abolished by mutation in the region of a putative glucocorticoid-responsive element. A similar interactive effect of Ang II and aldosterone was observed in cultured human umbilical vein endothelial cells. The time course of the effect of aldosterone on Ang II-induced PAI-1 expression was consistent with a classical mineralocorticoid receptor mechanism, and the effect of aldosterone on PAI-1 synthesis was attenuated by spironolactone. To determine whether aldosterone affected PAI-1 expression in vivo, we measured local venous PAI-1 antigen concentrations in six patients with primary hyperaldosteronism undergoing selective adrenal vein sampling. PAI-1 antigen, but not tissue plasminogen activator antigen, concentrations were significantly higher in adrenal venous blood than in peripheral venous blood. Taken together, these data support the hypothesis that aldosterone modulates the effect of Ang II on PAI-1 expression in vitro and in vivo in humans.

Metastatic follicular thyroid carcinoma masquerading as a chordoma.

A 61-year-old Caucasian man presented with otalgia, dysarthria, and weight loss. Neurological examination revealed palatal hypomotility, and weakness of the facial and tongue muscles. Magnetic resonance imaging of the head demonstrated the presence of a soft tissue mass in the clivus. Histologic examination of resected tumor disclosed well-differentiated thyroid follicles that invaded the local osseous tissues. Physical examination and radioiodine images of the thyroid gland were normal. The serum thyroglobulin concentration was markedly elevated (1011 ng/mL). A 0.9-cm well-differentiated benign-appearing left thyroid lobe follicular neoplasm with a thick fibrous capsule was found following diagnostic thyroidectomy. This report illustrates that clinically significant distant metastases can arise from occult follicular thyroid neoplasms that, according to standard histologic criteria, are benign. The presence of a thick fibrous capsule, even in the absence of vascular or capsular invasion, may identify follicular neoplasms that have metastatic potential.

Aggressive pituitary tumors.

Although almost all pituitary tumors are benign adenomas, a surprisingly large number of these tumors invade tissues outside of the pituitary gland. Such invasion, by itself, is not diagnostic of pituitary carcinomas, which are exceedingly rare (0.13% of 2,342 pituitary tumors in one series). Several different criteria are available to determine whether a tumor is invasive. Intraoperative biopsies demonstrate an 85% incidence of microscopic invasion of the dura. Evidence of gross invasion at surgery and radiologic evidence of invasion on magnetic resonance imaging (MRI) and computed tomographic (CT) scans occur at a much lower incidence but may be more predictive of surgical cure. Invasive adenomas also have higher proliferation rates than do noninvasive adenomas, as shown by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), Ki-67, and MIB-1. The expression of p53, increased epidermal growth factor receptors, and protein kinase C activity also correlate with invasion and aggressive behavior. Clinically significant invasion is more frequent with macroadenomas. Macroadenomas of all pituitary tumor subtypes except gonadotroph macroadenomas have a greater than 50% incidence of gross invasion. Currently, there is no accepted means of predicting an adenoma's clinically significant invasiveness and long-term aggressiveness.

Thromboembolic complications after inferior petrosal sinus sampling in patients with cushing's syndrome.

OBJECTIVE: To heighten the awareness of treating physicians of the potential for serious and fatal thromboembolic complications after inferior petrosal sinus sampling in patients with Cushing's syndrome. METHODS: We retrospectively reviewed inpatient and outpatient medical records for a 12-year period to identify patients with Cushing's syndrome who had thromboembolic complications after inferior petrosal sinus sampling at a single institution. Case reports of affected patients are presented. RESULTS: Of 34 patients with corticotropin-dependent Cushing's syndrome who underwent inferior petrosal sinus sampling, 2 had deep venous thrombosis. One of these patients succumbed to pulmonary thromboembolism. CONCLUSION: Serious and potentially fatal thromboembolic disorders may complicate inferior petrosal sinus sampling. Prospective studies should be undertaken to determine the true incidence of deep venous thrombosis after this procedure in patients with Cushing's syndrome.

Case report: reversible gastroparesis in patients with hypopituitary disease.

A 72-year-old woman with chronic fatigue, malaise, weight loss, nausea, and vomiting was treated unsuccessfully for gastroparesis for more than 2 years. Clinical and biochemical features of hypopituitary disease and symptoms of a nonsecreting pituitary tumor had been overlooked and became apparent only after the differential diagnosis of hyponatremia was considered. Transsphenoidal resection of the pituitary tumor and appropriate 1-thyroxine and hydrocortisone replacement returned her gastric emptying time to normal and relieved her symptoms. Primary and secondary deficits of l-thyroxine and cortisol should be considered when making a possible diagnosis of gastroparesis.

Naloxone-induced activation of the hypothalamic-pituitary-adrenal axis in suspected central adrenal insufficiency.

The authors studied 15 patients at risk for central adrenocortical insufficiency to evaluate the role of naloxone in establishing the integrity of the hypothalamic-pituitary-adrenal axis. Each patient was admitted to the General Clinical Research Center for 2 days. Naloxone, 125 micrograms/kg body weight, was administered intravenously, and plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at -15, 0, 30, 45, 60, 90, and 120 minutes. Metyrapone, 30 mg/kg body weight, was administered orally at 11 PM on the second day of hospitalization. Plasma ACTH, cortisol, and 11-deoxycortisol concentrations were measured at 8 AM pre- and postmetyrapone. The results of the metyrapone test were used to distinguish patients who had central adrenal insufficiency from those who were normal. In 11 patients who had a normal metyrapone test, the plasma ACTH level increased from 6 +/- 1 pmol/L at baseline to 11 +/- 2 pmol/L 30 minutes after naloxone administration. The plasma cortisol increased from 191 +/- 21 nmol/L at baseline to 379 +/- 47 nmol/L 45 minutes after naloxone administration. In four patients with central adrenal insufficiency, the plasma ACTH and cortisol concentrations did not increase after naloxone administration. Reliance solely on the individual ACTH and cortisol responses to naloxone would have permitted a correct decision regarding glucocorticoid replacement therapy in 14 (93%) of 15 patients. Naloxone stimulation testing may have a role in the clinical evaluation of patients with suspected central adrenocortical insufficiency.

Pancreatic polypeptide hypersecretion associated with a neuroendocrine carcinoma of the gallbladder.

The authors report a case of a suspected pure pancreatic polypeptide-secreting neuroendocrine carcinoma of the gallbladder. The tumor was initially interpreted as an adenocarcinoma of the gallbladder, but was found to have a neuroendocrine component after review. The pathology supports the view that a primitive epithelial stem cell can express both epithelial and neuroendocrine characteristics and can differentiate into both an adenocarcinoma and a neuroendocrine carcinoma. Upon recurrence, the tumor produced symptoms due to local growth, but eventually metastasized and led to the death of the patient within 4 years. The patient was treated with chemoembolization followed by the long-acting somatostatin analog octreotide acetate. The high serum level of pancreatic polypeptide may have contributed to cholestasis and cholelithiasis. Earlier measurement of serum hormone levels and identification of high pancreatic polypeptide levels may have suggested the presence of residual tumor and led to closer follow-up, imaging studies, and therapy.

Case report: acromegaly and Cushing's disease in a patient with synchronous pituitary adenomas.

A 40-year-old white woman presented with hirsutism, amenorrhea, generalized fatigue, diffuse weight gain, acral changes, and coarsened facial features. Physical examination revealed mild diastolic hypertension, acromegalic features, hirsutism, and seborrhea. The growth hormone concentration was elevated and did not suppress after glucose administration. Urinary free cortisol excretion was increased and was not suppressed during a 2 mg low-dose dexamethasone suppression test. Magnetic resonance imaging of the sella demonstrated a 1.3 x 1.2 x 0.8 cm pituitary adenoma. Trans-sphenoidal resection was performed, and portions of the resected tumor were analyzed by routine pathologic methods. Histopathologic and immunohistochemical findings indicated discrete growth hormone- and adrenocorticotropic hormone-producing pituitary adenomas. Coexisting acromegaly and Cushing's syndrome due to pituitary neoplasia was previously reported in two patients. However, to the authors' knowledge, this represents the first description of a patient with acromegaly and Cushing's disease resulting from discrete synchronous adenomas of the pituitary gland as defined by modern histopathologic techniques.

Diagnosis & management of pituitary tumors.

Pharmacologic agents are useful in the management of some patients with pituitary tumors. The diagnosis and management of pituitary adenomas are discussed.

Endocrinology.

We now have conclusive proof that intensive treatment reduces the microvascular complications of IDDM. ACE inhibitors appear to slow the progression of established nephropathy. Drug-induced malabsorption has the potential to increase levothyroxine dose requirement.

Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia.

A 24-year-old woman with ataxia-telangiectasia had traumatic arthritis, elevated serum transaminase values, polyuria, polydipsia, and a serum glucose level of 575 mg/dL. A relatively high daily dose of insulin (2.8 U/kg) was required to achieve near normoglycemia. The fasting insulin concentration was elevated. During an insulin-modified frequently sampled intravenous glucose tolerance test, the first phase of insulin release in response to the administration of glucose was blunted. The insulin sensitivity was similar to that found in individuals with non-insulin-dependent diabetes mellitus. Insulin receptor antibodies were not detected in the serum. We conclude that insulin resistance and islet beta-cell dysfunction are characteristics of diabetes mellitus in ataxia-telangiectasia. Contrary to a previous report, our findings do not support a cause-and-effect relationship between insulin receptor antibodies and insulin resistance in this disorder.